Henry Olivia J, Ygberg Sofia, Barbaro Michela, Lesko Nicole, Karlsson Leif, Peña-Pérez Lucía, Båvner Ann, Töhönen Virpi, Lindstrand Anna, Stödberg Tommy, Wedell Anna
Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
Center for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
Epilepsia. 2025 Aug;66(8):2966-2979. doi: 10.1111/epi.18403. Epub 2025 Apr 4.
A large proportion of pediatric epilepsies have an underlying genetic etiology. Limited studies have explored the efficacy of whole genome sequencing (WGS) in a clinical setting. Our academic-clinical center implemented clinical whole exome sequencing (WES) in 2014, then transitioned to WGS from 2015. We report the diagnostic yield, genetic and phenotypic findings, and prognostic factors following WGS/WES in pediatric epilepsy.
The cohort included 733 families with pediatric epilepsy who received clinical WGS/WES between 2014 and 2022. WGS/WES was performed at the Genomic Medicine Center Karolinska for Rare Diseases and analyzed at the Center for Inherited Metabolic Diseases at Karolinska University Hospital. Phenotypic information was extracted from referrals and medical records. Genetic and phenotypic data were analyzed using descriptive statistics, and univariable and multivariable analyses.
The median age at seizure onset was 9 months. Developmental delay and/or intellectual disability (DD/ID) was observed in 61.3% of the cohort; 38.1% of individuals received an International League Against Epilepsy epilepsy syndrome diagnosis. WGS/WES was performed in 640 (87.3%) and 143 (19.5%) families, respectively, totaling 2029 individuals. A molecular diagnosis was identified in 278 of 733 individuals (37.9%), including 51 of 211 individuals analyzed more than once (24.2% of reanalyzed cases). Independent predictors for receiving a genetic diagnosis included female sex (adjusted odds ratio [aOR] = 1.8, 95% confidence interval [CI] = 1.3-2.4, p < .001), neonatal seizure onset (aOR = 2.5, 95% CI = 1.6-4, p < .001), mortality (aOR = 2.2, 95% CI = 1.3-4.0, p = .0048), and an ID/DD/developmental and epileptic encephalopathy (DEE) diagnosis (aOR = 1.8, 95% CI = 1.2-2.5, p = .0019). The strongest independent predictor of ID/DD/DEE was microcephaly (aOR = 7.8, 95% CI = 2-53, p = .0099). In the solved cohort, gene group did not predict cognitive outcome.
Clinical WGS is an effective diagnostic tool in pediatric epilepsy. We identified female sex as a novel prognostic factor for receiving a genetic diagnosis and highlight the value of reanalyzing previously unsolved cases to improve diagnostic yield.
大部分小儿癫痫具有潜在的遗传病因。有限的研究探索了全基因组测序（WGS）在临床环境中的有效性。我们的学术临床中心于2014年实施了临床全外显子组测序（WES），然后从2015年开始过渡到WGS。我们报告小儿癫痫患者进行WGS/WES后的诊断率、遗传和表型发现以及预后因素。
该队列包括733个患有小儿癫痫的家庭，这些家庭在2014年至2022年间接受了临床WGS/WES。WGS/WES在卡罗林斯卡罕见病基因组医学中心进行，并在卡罗林斯卡大学医院的遗传代谢疾病中心进行分析。从转诊和医疗记录中提取表型信息。使用描述性统计、单变量和多变量分析对遗传和表型数据进行分析。
癫痫发作开始的中位年龄为9个月。队列中61.3%的患者出现发育迟缓或智力残疾（DD/ID）；38.1%的个体获得了国际抗癫痫联盟癫痫综合征诊断。分别对640个（87.3%）和143个（19.5%）家庭进行了WGS/WES，共涉及2029名个体。在733名个体中的278名（37.9%）中确定了分子诊断，其中在211名多次分析的个体中有51名（重新分析病例的24.2%）。获得遗传诊断的独立预测因素包括女性（调整优势比[aOR]=1.8，95%置信区间[CI]=1.3 - 2.4，p<.001）、新生儿癫痫发作（aOR = 2.5，95% CI = 1.6 - 4，p<.001）、死亡率（aOR = 2.2，95% CI = 1.3 - 4.0，p = .0048）以及ID/DD/发育性和癫痫性脑病（DEE）诊断（aOR = 1.8，95% CI = 1.2 - 2.5，p = .0019）。ID/DD/DEE最强的独立预测因素是小头畸形（aOR = 7.8，95% CI = 2 - 53，p = .0099）。在已解决的队列中，基因组不能预测认知结果。
临床WGS是小儿癫痫的一种有效诊断工具。我们确定女性是获得遗传诊断的一个新的预后因素，并强调重新分析先前未解决病例以提高诊断率的价值。
